This invention relates to thiophene compounds which are novel and useful pharmaceuticals and their pharmaceutical uses, and the synthetic intermediates therefor.
Benzodiazepine (BZP) derivatives represented by diazepam have been used as an antianxiety drug or a therapeutic medicine for sleep disturbance. The BZP receptor was discovered in 1977 [Science, vol. 198, 848 (1977)] and extensive research has been done to focus upon the mechanism of the drug's action in relation to anxiety. It has been made clear that BZP receptor ligands can differ in their allosteric modulatory effect on the gating of the GABA.sub.A receptor coupled chloride channel. It has been proposed that BZP receptor ligands which act to enhance GABA.sub.A receptor function be called BZP agonists, those which act to reduce GABA.sub.A receptor be called BZP inverse agonists, and those which neither appreciably augment nor attenuate the GABA.sub.A gating function (but can block the effects of BZP agonists and BZP inverse agonists) be called BZP antagonists. These three categories of BZP receptor ligands can be considered to have full positive, full negative, or zero intrinsic efficacy, respectively. BZP partial agonists (or BZP partial inverse agonists) exhibit intermediate intrinsic efficacy. Thus, BZP partial agonists (or BZP partial inverse agonists) bind to the BZP receptor but not all ligand-receptor complexes exert a functional effect. As a result it is possible to conceive of BZP partial agonists which, due to differential tissue receptor reserves, exhibit a more selective (e.g., anxioselective) pharmacological profile.
BZP derivatives which are used as antianxiety drugs have various effects such as sedative action, muscle-relaxation effect and potentiation action of narcotic and alcoholic effects in addition to antianxiety action. Consequently, they often cause side effects such as dizziness and sleepness. Thus, the extensive investigations are carried on to develop selective antianxiety drugs of the non-BZP types with less side effects.
Also, recently, it has been known that BZP agonists induce amnesic action [Nature, vol. 321, 864 (1986)], and the possibility has been suggested that BZP antagonists and BZP inverse-agonists are usable as nootropics since the former antagonize BZP agonists and the latter exhibit an action reverse to BZP agonists [Trends in Neurosciences, vol. 11, 13 (1988)].
In the specification of U.S. Pat. No. 4,843,075 there are disclosed useful benzothiopyrano [4,3-c]pyridazine compounds as antianxiety drugs. U.S. Pat. No. 4,849,421 discloses benzothiepino[5,4-c]pyridazine compounds which exhibit selective antianxiety activity. In particular, 2-(4-chlorophenyl)-5,6-dihydro[1]benzothiepino[5,4-c]pyridazin-3(2H)-one described in this U.S. Patent specification shows partial agonistic activity against BZP receptors and is expected clinically as a selective antianxiety drug. Further, European Patent Application No. 308,515 discloses thienocinnoline compounds useful as antianxiety drugs or antidementiac drugs.